By inhibiting MAO activity, MAO inhibitors can regulate the level of monoamines and their neurotransmitter release in different brain regions and in the body (including dopamine, norepinephrine, and serotonin). Thus, MAO inhibitors can affect the modulation of neuroendocrine function, respiration, mood, motor control and function, focus and attention, concentration, memory and cognition, and the mechanisms of substance abuse. Inhibitors of MAO have been demonstrated to have effects on attention, cognition, appetite, substance abuse, memory, cardiovascular function, extrapyramidal function, pain and gastrointestinal motility and function. The distribution of MAO in the brain is widespread and includes the basal ganglia, cerebral cortex, limbic system, and mid and hind-brain nuclei. In the peripheral tissue, the distribution includes muscle, the gastrointestinal tract, the cardiovascular system, autonomic ganglia, the liver, and the endocrinic system. The present invention overcomes the problems and limitations of the prior art by providing methods and systems.
MAO inhibition by other inhibitors have been shown to increase monoamine content in the brain and body. Regulation of monoamine levels in the body have been shown to be effective in numerous disease states including depression, anxiety, stress disorders, diseases associated with memory function, neuroendocrine problems, cardiac dysfunction, gastrointestinal disturbances, eating disorders, hypertension, Parkinson's disease, memory disturbances, and withdrawal symptoms.
It has been suggested that cigarette smoke may have irreversible inhibitory effect towards monoamine oxidase (MAO). A. A. Boulton, P. H. Yu and K. F. Tipton, “Biogenic Amine Adducts, Monoamine Oxidase Inhibitors, and Smoking,” Lancet, 1(8577): 114-155 (Jan. 16, 1988), reported that the MAO-inhibiting properties of cigarette smoke may help to explain the protective action of smoking against Parkinson's disease and also observed that patients with mental disorders who smoke heavily do not experience unusual rates of smoking-induced disorders. It was suggested that smoking, as an MAO inhibitor, may protect against dopaminergic neurotoxicity that leads to Parkinson's disease and that the MAO-inhibiting properties of smoking may result in an anti-depressive effect in mental patients.
L. A. Carr and J. K. Basham, “Effects of Tobacco Smoke Constituents on MPTP Induced Toxicity and Monoamine Oxidase Activity in the Mouse Brain,” Life Sciences, 48:1173-1177 (Jan. 16, 1991), found that nicotine, 4-phenylpyridine and hydrazine prevented the decrease in dopamine metabolite levels induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice, but there was no significant effect on dopamine levels. Because tobacco smoke particulate matter caused a marked inhibition of MAO A and MAO B activity when added in vitro, it was suggested that one or more unidentified substances in tobacco smoke are capable of inhibiting brain MAO and perhaps altering the formation of the active metabolite of MPTP.
J. S. Fowler, N. D. Volkow, G. J. Wang, N. Pappas, and J. Logan, “Inhibition of Monoamine Oxidase B in the Brain of Smokers,” Nature (Lond), 379(6567):733-736 (Feb. 22, 1996), found that the brains of living smokers showed a 40% decrease in the level of MAO B relative to non-smokers or former smokers. MAO inhibition was also reported as being associated with decreased production of hydrogen peroxide.
It has also been suggested that nicotine may not be the only constituent of tobacco responsible for tobacco addiction. J. Stephenson, “Clues Found to Tobacco Addiction,” Journal of the American Medical Association, 275(16): 1217-1218 (Apr. 24, 1996), discussing the work of Fowler, et al., pointed out that the brains of living smokers had less MAO B compared with the brains of nonsmokers or former smokers. MAO B is an enzyme involved in the breakdown of dopamine, which is a pleasure-enhancing neurotransmitter. The results suggested that the inhibition of MAO B in the brains of smokers may make nicotine more addictive by slowing down the breakdown of dopamine, thereby boosting its levels. The findings provided an explanation as to why cigarette smokers were less susceptible to developing Parkinson's disease. Further, the findings suggested that MAO inhibitors could be used for smoking cessation.
K. R. R. Krishnan, “Monoamine Oxidase Inhibitors,” The American Psychiatric Press Textbook of Pharmacology, American Psychiatric Press, Inc., Washington, D.C. 1995, pp. 183-193, suggest various uses for monoamine oxidase inhibitors. The uses include atypical depression, major depression, dysthymia, melancholia, panic disorder, bulimia, atypical facial pain, anergic depression, treatment-resistant depression, Parkinson's disease, obsessive-compulsive disorder, narcolepsy, headache, chronic pain syndrome, and generalized anxiety disorder.
D. Nutt and S. A. Montgomery, “Moclobemide in the Treatment of Social Phobia,” Int. Clin. Psychopharmacol, 11 Suppl. 3: 77-82 (Jun. 11, 1996), reported that moclobemide, a reversible MAO inhibitor, may be effective in the treatment of social phobia.
I. Berlin, et al., “A Reversible Monoamine Oxidase A Inhibitor (Moclobemide) Facilitates Smoking Cessation and Abstinence in Heavy, Dependent Smokers,” Clin. Pharmacol. Ther., 58(4): 444-452 (October 1995), suggested that a reversible MAO A inhibitor can be used to facilitate smoking cessation.
U.S. Pat. No. 3,870,794 discloses the administering of small quantities of nicotine and nicotine derivatives to mammals, including humans, to reduce anger and aggressiveness and to improve task performance.
U.S. Pat. No. 5,276,043 discloses the administering of an effective amount of certain anabasine compounds, certain unsaturated anabasine compounds, or unsaturated nicotine compounds to treat neurodegenerative diseases.
U.S. Pat. No. 5,516,785 disclose a method of using anabasine, and DMAB anabasine for stimulating brain cholinergic transmission and a method for making anabasine.
U.S. Pat. Nos. 5,594,011, 5,703,100, 5,705,512, and 5,723,477 disclose modulators of acetylcholine receptors.
Known irreversible MAO inhibitors also inhibit MAO in the stomach and liver as well as the brain. As a result, their use has been limited because hypertensive crisis may occur when certain types of food (for example, fermented foods) are ingested, thereby creating an adverse drug-food interaction. Tyramine, which has a pressor action and which is normally broken down by the MAO enzymes, can be present in certain foods.
Thus, it would be desirable to provide MAO inhibitors which are effective, but less potent (i.e., those which provide an asymptotic effect on MAO inhibition) than known MAO inhibitors, for the treatment-of various conditions and disorders. It would also be desirable to provide MAO inhibitors which are easily synthesized and which could be provided to patients as an “over the counter” medication or dietary supplement.